High genetic heterogeneity in mitochondrial disorders

Posted comment on ´Targeted exome sequencing for mitochondrial disorders reveals high genetic heterogeneity` by J.T. DaRe, V. Vasta, J. Penn, N.-T.B. Tran and S. H. Hahn published in BMC Medical Genetics 2013, 14: 118 doi:10.1186/1471-2350-14-118

In this paper the authors are expanding on previous work using targeted next-generation sequencing (TNGS) as a possible diagnostic tool for mitochondrial disorders. Using 148 patients with diagnosed or suspected mitochondrial disorders and their parents and TNGS they looked at a gene panel of 83 genes possibly involved in critical mitochondrial functions and 364 genes known to be involved in mitochondrial disorders.
They found on average 553 variants per patient within the targeted regions with synonymous single nucleotide substitutions being the most common. The team identified variants possibly disease-causing in 12 genes in 13 patients. Eleven of the twenty-one variants were already acknowledged as disease-causing mutations, for example in the gene MTFMT (for Leigh syndrome) or gene NDUFS2 (for mitochondrial complex I deficiency), and they found variants in the NDUFS2 gene encoding for oxidative phosphorylation subunit of complex I, the gene NDUFAF5 for the assembly of the complex I and one gene in the group relating mitochondrial disease causative genes (the gene SCO2).
Limited parental testing was performed in cases of variants of unknown significance. From 15 potentially compound heterozygous variants, the team identified eight consistent with autosomal recessive disease (AR) inheritance. In one parent there were 19 out of 20 variants, in another the gene KIF1B variant, and in patients with XL disease parents had variants in the genes CDKL5 and DCX. This puts a question mark over the validity of using this type of test for mitochondrial disease diagnosis since if a variant is found in both patient and healthy parent, then it is unlikely that this is a pathogenic mutation.
DaRe and colleagues concluded that targeted next-generation sequencing is a valuable tool in aiding diagnosis of patients with mitochondrial disease, but there appears to be a high level of genetic heterogeneity in mitochondrial DNA which makes definitive disease diagnosis using this method difficult. Indeed, some patients suspected of mitochondrial disease exhibit secondary inhibition of mitochondrial function or have mutations in genes that actually do not impair mitochondrial function. The team suggests further examination of the mitochondrial gene variants particularly since they noticed that some patients had variants in multiple genes suggesting that the disease may not be the result of deficiency in one mitochondrial factor, but many.
The availability of a nice concrete laboratory test that would take the indecision about any diagnosis of disease is always welcome and first reports led to the hope that targeted next-generation sequencing (TNGS) would fit that demand in the case of mitochondrial diseases. DaRe and colleagues previous study on about 900 known and suspected mitochondrial disease related genes with a study group of 26 diagnosed patients showed that TNGS was analytically sensitive enough to be clinically useful as a diagnosis tool. Therefore, it is disappointing that what should have been an investigation to define specificity even further actually ended up making the picture less clear – a smaller gene panel, larger patient number and now a high level of genetic heterogeneity. For a biochemist, it is probably not surprising since there are a vast number of mitochondrial genes for a vast number of proteins, processes and feedback mechanisms for an organelle of extreme cellular importance. Therefore, it is likely that high variation of genetic code can exist without devastating effects on mitochondrial structure and function. And this is indeed what the DaRe team found – overlapping functions, incidences of genetic variation in parents and patients, multiple factors bringing about the overall mitochondrial structure and function. However, mitochondrial diseases exist and the DaRe team and others are gradually clarifying the genetic picture relating to them.
Since we`re chatting about the subject…….
…can we assume that the mitochondrial deficiencies observed in this type of disease are observed in all human cells and are not organ specific?
….it is logical that there are balancing mechanisms in play in the mitochondria to combat abnormal conditions (eg like those relating to increased production of the reactive oxygen species), but these must be either overridden or defective in the case of mitochondrial disease and maybe we should be looking at the genetics of these as well as the genes relating to the primary structure and function.

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